Biology Reference
In-Depth Information
IL-18
IL-18 is a member of the IL-1 family and is produced by a variety of both
hematopoietic and nonhematopoietic cells, including macrophages,
peripheral blood mononuclear cells (PBMC), DC, T lymphocytes, kerati-
nocytes, and intestinal epithelial cells
[98]
. IL-18 was originally discovered
as a factor that influences IFN-γ production from donor T cells under the
influence of IL-12. However, it is now clear that IL-18 predominantly acts
to promote IL-12 production, but, of note, can also promote Th2 responses
in the absence of IL-12
[98]
. It is also known to promote Th1 responses and
improve CTL function.
In animal models, IL-18 has been shown to promote engraftment and
persistence of effector T in a xenogeneic model of GVHD
[99]
. There are
preclinical data to suggest that IL-18 administration has a role in the pre-
vention of cGVHD
[100]
; however, this is less clear in aGVHD. Serial studies
by the same group report a highly model-specific beneficial role for IL-18
administration, with beneficial effects seen specifically in MHC II-dispa-
rate, CD4-dependent GVHD models
[101]
and the opposite effect seen in
CD8-dependent GVHD. In mouse models dependent on CD8 T cells for
GVHD development, blockade of IL-18 was in fact found to be beneficial
with respect to GVHD outcome.
370
Clinically, increased serum levels of IL-18 have been demonstrated in GVHD
and were shown to be predictive of aGVHD severity
[102,103]
. Given these
data, and the model dependence of IL-18-mediated GVHD protection, it is
unlikely that this cytokine could be safely administered in the clinical setting.
Cytokines involved in Th2 differentiation
IL-4
IL-4 is a classic “Th2”-inducing cytokine that signals through a unique
IL-4R coupled with the γ
c
chain, in a manner similar to that of the other
common-γ-chain cytokine family. Intracellular signaling is propagated by
JAK/STAT signaling, and while multiple JAK molecules can partake in sig-
naling (JAK1-3), STAT6 is the critical molecule for downstream signal trans-
duction
[104]
. It is predominantly produced by CD4
+
Th2 lineage T cells,
but can also be secreted by NKT cells, basophils, and mast cells. IL-4 plays
a role in altering the differentiation pattern of cytokine-stimulated naïve T
cells toward a Th2 pattern and the subsequent production of further IL-4,
as well as IL-5, IL-10, and IL-13
[105,106]
. Of note, IL-4 is a critical negative
regulator of Th1 development.
PRECLINICAL EVIDENCE FOR IL-4 IN GVHD AND GVL
Preclinical models using mice incapable of IL-4 signaling (STAT6 deficient)
have shown that Th2 cells and cytokines can be pathogenic in GVHD and
contribute to mortality
[107]
. It has also recently been reported that adop-
tive transfer of NKT cells could suppress aGVHD via secretion of IL-4, which
did not alter proliferation of effector T cells, but significantly reduced their
capacity to produce IFN-γ and TNF
[108]
. The authors of this study showed
that their NKT delivery regimen had no negative impact on GVL effects.
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